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WO2010112193A1 - Anticorps multispécifiques renfermant des anticorps de longueur entière et des fragments fab à chaîne unique - Google Patents

Anticorps multispécifiques renfermant des anticorps de longueur entière et des fragments fab à chaîne unique Download PDF

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Publication number
WO2010112193A1
WO2010112193A1 PCT/EP2010/002004 EP2010002004W WO2010112193A1 WO 2010112193 A1 WO2010112193 A1 WO 2010112193A1 EP 2010002004 W EP2010002004 W EP 2010002004W WO 2010112193 A1 WO2010112193 A1 WO 2010112193A1
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Prior art keywords
antibody
full length
binding
antibodies
antigen
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Inventor
Ulrich Brinkmann
Peter Bruenker
Rebecca Croasdale
Christian Klein
Erhard Kopetzki
Ekkehard Moessner
Joerg Thomas Regula
Juergen Michael Schanzer
Jan Olaf Stracke
Pablo Umana
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Roche Glycart AG
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Roche Glycart AG
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Priority to RU2011143905/10A priority Critical patent/RU2598248C2/ru
Priority to MX2011010159A priority patent/MX2011010159A/es
Priority to BRPI1014089A priority patent/BRPI1014089A2/pt
Priority to KR1020117025868A priority patent/KR101431318B1/ko
Priority to JP2012502505A priority patent/JP5501439B2/ja
Priority to CA 2756244 priority patent/CA2756244A1/fr
Priority to EP10711847.3A priority patent/EP2414391B1/fr
Priority to HK12108390.5A priority patent/HK1167669B/xx
Priority to CN201080015592.4A priority patent/CN102369215B/zh
Priority to SG2011071479A priority patent/SG175004A1/en
Application filed by Roche Glycart AG filed Critical Roche Glycart AG
Priority to AU2010230563A priority patent/AU2010230563A1/en
Publication of WO2010112193A1 publication Critical patent/WO2010112193A1/fr
Priority to IL214756A priority patent/IL214756A0/en
Priority to ZA2011/06666A priority patent/ZA201106666B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/626—Diabody or triabody
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • Multispecific antibodies comprising full length antibodies and single chain Fab fragments
  • the present invention relates to multispecific, especially bispecific antibodies comprising full length antibodies and single chain Fab fragments, methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.
  • a wide variety of multispecific recombinant antibody formats have been developed in the recent past, e.g. tetravalent bispecific antibodies by fusion of, e.g., an IgG antibody format and single chain domains (see e.g. Coloma, MJ. , et al., Nature Biotech 15 (1997) 159-163; WO 2001/077342; and Morrison, S.L., Nature Biotech 25 (2007) 1233-1234).
  • All such formats use linkers either to fuse the antibody core (IgA, IgD, IgE, IgG or IgM) to a further binding protein (e.g. scFv) or to fuse e.g. two Fab fragments or scFvs (Fischer, N., Leger, O., Pathobiology 74 (2007) 3-14). It has to be kept in mind that one may want to retain effector functions, such as e.g. complement- dependent cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC), which are mediated through the Fc receptor binding, by maintaining a high degree of similarity to naturally occurring antibodies.
  • CDC complement- dependent cytotoxicity
  • ADCC antibody dependent cellular cytotoxicity
  • WO 2007/024715 are reported dual variable domain immunoglobulins as engineered multivalent and multispecific binding proteins.
  • a process for the preparation of biologically active antibody dimers is reported in US 6,897,044.
  • Multivalent F v antibody construct having at least four variable domains which are linked with each over via peptide linkers are reported in US 7,129,330.
  • Dimeric and multimeric antigen binding structures are reported in US 2005/0079170.
  • Tri- or tetra-valent monospecific antigen-binding protein comprising three or four Fab fragments bound to each other covalently by a connecting structure, which protein is not a natural immunoglobulin are reported in US 6,511,663.
  • bispecific antibodies are reported that can be efficiently expressed in prokaryotic and eukaryotic cells, and are useful in therapeutic and diagnostic methods.
  • a method of separating or preferentially synthesizing dimers which are linked via at least one interchain disulfide linkage from dimers which are not linked via at least one interchain disulfide linkage from a mixture comprising the two types of polypeptide dimers is reported in US 2005/0163782.
  • Bispecific tetravalent receptors are reported in US 5,959,083.
  • Engineered antibodies with three or more functional antigen binding sites are reported in WO 2001/077342.
  • Multispecific and multivalent antigen-binding polypeptides are reported in WO 1997/001580.
  • WO 1992/004053 reports homoconjugates, typically prepared from monoclonal antibodies of the IgG class which bind to the same antigenic determinant are covalently linked by synthetic cross-linking.
  • Oligomeric monoclonal antibodies with high avidity for antigen are reported in WO 1991/06305 whereby the oligomers, typically of the IgG class, are secreted having two or more immunoglobulin monomers associated together to form tetravalent or hexavalent IgG molecules.
  • Sheep-derived antibodies and engineered antibody constructs are reported in US 6,350,860, which can be used to treat diseases wherein interferon gamma activity is pathogenic.
  • US 2005/0100543 are reported targetable constructs that are multivalent carriers of bi-specific antibodies, i.e., each molecule of a targetable construct can serve as a carrier of two or more bi-specific antibodies.
  • Genetically engineered bispecific tetravalent antibodies are reported in WO 1995/009917.
  • stabilized binding molecules that consist of or comprise a stabilized scFv are reported.
  • a first aspect of the current invention is a multispecific antibody comprising
  • a preferred aspect of the current invention is a multispecific antibody comprising
  • the said multispecific antibody comprises one or two single chain Fab fragments binding to a second antigen (bispecific antibody).
  • the said multispecific antibody comprises two single chain Fab fragments binding to a second antigen (bispecific antibody).
  • the said multispecific antibody comprise two single chain Fab fragments binding to a second antigen and a third antigen (trispecific antibody).
  • a further aspect of the invention is a nucleic acid molecule encoding a chain of said multispecific antibody wherein a single chain Fab fragment is fused to the C- or N- terminus of the heavy or light chain of said full length antibody.
  • Still further aspects of the invention are a pharmaceutical composition comprising said multispecific antibody.
  • the multispecific antibodies according to the invention showed valuable properties such as a high stability, low aggregation tendency (see e.g. Example 2 (e.g. compared to a full length antibody to which two scFv fragments are fused via a peptide linker at the C-terminus of the heavy chain (see WO 1995/009917 or M ⁇ ller, D., et al., Handbook of Therapeutic antibodies, Part III, Chapter 2, (2008) 345-378).
  • the multispecific antibodies according to the invention one the one hand show new properties due to their binding to different antigens, and on the other hand are suitable for production and pharmaceutical formulation due to their good stability, low aggregation and valuable pharmacokinetic and biological properties. Due to their Ig core and ability to be produced in mammalian expression systems they still retain the properties of natural antibodies like ADCC and CDC.
  • a first aspect of the current invention is a multispecific antibody comprising
  • a preferred aspect of the current invention is a multispecific antibody comprising
  • single chain Fab fragments under b) are fused to said full length antibody under a) via a peptide connector at the C- or N- terminus of the heavy or light chain of said full length antibody.
  • one or two identical single chain Fab fragments binding to a second antigen are fused to said full length antibody via a peptide connector at the C-terminus of the heavy or light chains of said full length antibody.
  • one or two identical single chain Fab fragments binding to a second antigen are fused to said full length antibody via a peptide connector at the C-terminus of the light chains of said full length antibody.
  • two identical single chain Fab fragments binding to a second antigen are fused to said full length antibody via a peptide connector at the C- terminus of each heavy or light chain of said full length antibody.
  • two identical single chain Fab fragments binding to a second antigen are fused to said full length antibody via a peptide connector at the C- terminus of each heavy chain of said full length antibody.
  • two identical single chain Fab fragments binding to a second antigen are fused to said full length antibody via a peptide connector at the C- terminus of each light chain of said full length antibody.
  • full length antibody denotes an antibody consisting of two “full length antibody heavy chains” and two “full length antibody light chains” (see Fig. 1).
  • full length antibody heavy chain is a polypeptide consisting in N-terminal to C-terminal direction of an antibody heavy chain variable domain (VH), an antibody constant heavy chain domain 1 (CHl), an antibody hinge region (HR), an antibody heavy chain constant domain 2 (CH2), and an antibody heavy chain constant domain 3 (CH3), abbreviated as VH-CH 1-HR-CH2-CH3; and optionally an antibody heavy chain constant domain 4 (CH4) in case of an antibody of the subclass IgE.
  • VH antibody heavy chain variable domain
  • CHl antibody constant heavy chain domain 1
  • HR antibody heavy chain constant domain 2
  • CH3 antibody heavy chain constant domain 3
  • VH-CH 1-HR-CH2-CH3 an antibody heavy chain constant domain 4 (CH4) in case of an antibody of the subclass IgE.
  • the "full length antibody heavy chain” is a polypeptide consisting in N-terminal to C-terminal direction of VH, CHl, HR, CH2 and CH3.
  • a “full length antibody light chain” is a polypeptide consisting in N-terminal to C-terminal direction of an antibody light chain variable domain (VL), and an antibody light chain constant domain (CL), abbreviated as VL-CL.
  • the antibody light chain constant domain (CL) can be K (kappa) or ⁇ (lambda).
  • the two full length antibody chains are linked together via inter-polypeptide disulfide bonds between the CL domain and the CHl domain and between the hinge regions of the full length antibody heavy chains.
  • Examples of typical full length antibodies are natural antibodies like IgG (e.g. IgG 1 and IgG2), IgM, IgA, IgD, and IgE.
  • the full length antibodies according to the invention can be from a single species e.g. human, or they can be chimerized or humanized antibodies.
  • the full length antibodies according to the invention comprise two antigen binding sites each formed by a pair of VH and VL, which both specifically bind to the same antigen.
  • the C-terminus of the heavy or light chain of said full length antibody denotes the last amino acid at the C-terminus of said heavy or light chain.
  • the N-terminus of the heavy or light chain of said full length antibody denotes the last amino acid at the N- terminus of said heavy or light chain.
  • a “single chain Fab fragment” is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CHl), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein said antibody domains and said linker have one of the following orders in N-terminal to C-terminal direction: a) VH-CHl -linker- VL-CL, b) VL-CL-linker-VH-CHl, c) VH-C L-linker- VL-CHl or d) VL-CH 1 -linker- VH-CL; and wherein said linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids.
  • Said single chain Fab fragments a) VH-CH l-linker- VL-CL, b) VL-CL-linker-VH-CHl, c) VH-CL- linker- VL-CHl and d) VL-CH l-linker- VH-CL, are stabilized via the natural disulfide bond between the CL domain and the CHl domain.
  • N-terminus denotes the last amino acid of the N-terminus
  • C-terminus denotes the last amino acid of the C-terminus.
  • said antibody domains and said linker in in said single chain Fab fragment have one of the following orders in N-terminal to C-terminal direction: a) VH-CH l-linker- VL-CL, or b) VL-CL-linker-VH-CHl, more preferably VL-CL- linker-VH-CHl.
  • said antibody domains and said linker in in said single chain Fab fragment have one of the following orders in N-terminal to C-terminal direction: a) VH-CL-linker- VL-CHl or b) VL-CH l-linker- VH-CL.
  • the antibody heavy chain variable domain (VH) and the antibody light chain variable domain (VL) are disulfide stabilized by introduction of a disulfide bond between the following positions: i) heavy chain variable domain position 44 to light chain variable domain position 100, ii) heavy chain variable domain position 105 to light chain variable domain position 43, or iii) heavy chain variable domain position 101 to light chain variable domain position 100 (numbering always according to EU index of Kabat).
  • Such further disulfide stabilization of single chain Fab fragments is achieved by the introduction of a disulfide bond between the variable domains VH and VL of the single chain Fab fragments.
  • Techniques to introduce unnatural disulfide bridges for stabilization for a single chain Fv are described e.g. in WO 94/029350, Rajagopal,
  • the optional disulfide bond between the variable domains of the single chain Fab fragments comprised in the antibody according to the invention is between heavy chain variable domain position 44 and light chain variable domain position 100.
  • the optional disulfide bond between the variable domains of the single chain Fab fragments comprised in the antibody according to the invention is between heavy chain variable domain position 105 and light chain variable domain position 43 (numbering always according to EU index of Kabat).
  • single chain Fab fragment without said optional disulfide stabilization between the variable domains VH and VL of the single chain Fab fragments are preferred.
  • peptide connector denotes a peptide with amino acid sequences, which is preferably of synthetic origin. These peptide connectors according to invention are used to fuse the single chain Fab fragments to the C-or N-terminus of the full length antibody to form a multispecific antibody according to the invention.
  • said peptide connector is (G 4 S) 2 .
  • linker denotes a peptide with amino acid sequences, which is preferably of synthetic origin. These peptides according to invention are used to link a) VH-CHl to VL-CL, b) VL-CL to VH-CHl, c) VH-CL to VL-CHl or d) VL-CHl to VH-CL to form the following single chain Fab fragments according to the invention a) VH-CHl -linker- VL-CL, b) VL-CL-linker- VH-CHl, c) VH-CL-linker- VL-CHl or d) VL-CHl -linker- VH-CL.
  • Said linker within the single chain Fab fragments is a peptide with an amino acid sequence with a length of at least 30 amino acids, preferably with a length of 32 to 50 amino acids.
  • said linker is (G 4 S) 6 G 2 .
  • the multispecific antibody according to the invention comprises one to four single chain Fab fragments. More preferably the multispecific antibody according to the invention comprises two identical single chain Fab fragments (preferably VL-CL-linker-VH-CHl) which are both fused to the two C-termini of the two heavy chains or to the two C-termini of the two light chains of said full length antibody under a).
  • Such fusion results in two identical fusion peptides (either i) heavy chain and single chain Fab fragment or ii) light chain and single chain Fab fragment) which are coexpressed with either i) the light chain or the heavy chain of the full length antibody to give the multispecific antibody according to the invention (see Fig. 3, 4 and 5).
  • the multispecific antibody according to the invention comprises two identical single chain Fab fragments (preferably VH-CHl- linker- VL-CL) which are both fused to the two N-termini of the two heavy chains or to the two N-termini of the two light chains of said full length antibody under a).
  • Such fusion results in two identical fusion peptides (either i) heavy chain and single chain Fab fragment or ii) light chain and single chain Fab fragment) which are coexpressed with either i) the light chain or the heavy chain of the full length antibody to give the multispecific antibody according to the invention.
  • Both parts of the multispecific antibody according to the invention comprise antigen-binding sites (the full length antibody according the invention comprises two, and each single chain Fab fragment comprises one antigen binding site).
  • binding site or "antigen-binding site” as used herein denotes the region(s) of said multispecific antibody according to the invention to which the respective antigen actually specifically binds.
  • the antigen binding sites either in the full length antibody or in the single chain Fab fragment are formed each by a pair consisting of an antibody light chain variable domain (VL) and an antibody heavy chain variable domain (VH).
  • the antigen-binding sites that specifically bind to the desired antigen can be derived a) from known antibodies to the antigen (e.g anti-EGFR antibodies) or b) from new antibodies or antibody fragments obtained by de novo immunization methods using inter alia either the antigen protein or nucleic acid or fragments thereof or by phage display.
  • An antigen-binding site of an antibody of the invention contains six complementarity determining regions (CDRs) which contribute in varying degrees to the affinity of the binding site for antigen. There are three heavy chain variable domain CDRs (CDRHl, CDRH2 and CDRH3) and three light chain variable domain CDRs (CDRLl, CDRL2 and CDRL3). The extent of CDR and framework regions (FRs) is determined by comparison to a compiled database of amino acid sequences in which those regions have been defined according to variability among the sequences.
  • Antibody specificity refers to selective recognition of the antibody for a particular epitope of an antigen. Natural antibodies, for example, are monospecific.
  • the term "multispecific” antibody as used herein denotes an antibody that has two or more anigen-binding sites of which at least two bind to a different antigen or a different epitope of the same antigen.
  • "Bispecific antibodies” according to the invention are antibodies which have two different antigen-binding specificities.
  • Antibodies of the present invention are e.g. multispecific for at least two different antigens, i.e. EGFR as first antigen and IGF-IR as second antigen. In one embodiment of the invention the multispecific antibody according to the invention is bispecific. In another embodiment of the invention the multispecific antibody according to the invention is trispecific.
  • monospecific antibody denotes an antibody that has one or more binding sites each of which bind to the same epitope of the same antigen.
  • the term "valent” as used within the current application denotes the presence of a specified number of binding sites in an antibody molecule.
  • a natural antibody for example or a full length antibody according to the invention has two binding sites and is bivalent.
  • the terms “trivalent”, “tetravalent”, “pentavalent” and “hexavalent” denote the presence of two binding site, three binding sites, four binding sites, five binding sites, and six binding sites, respectively, in an antibody molecule.
  • the multispecific antibodies according to the invention are at least “trivalent”. Preferably they are “trivalent”, “tetravalent”, “pentavalent” or “hexavalent”, more preferably they are “trivalent” or "tetravalent”.
  • Antibodies of the present invention have three or more binding sites and are multispecific, preferably bispecific or trispecific As the multispecific antibodies according to the invention may be bispecific even in cases where there are more than three binding sites (i.e. that the antibody is tetravalent, pentavalent or hexavalent or multivalent). For an antibody with more than two antigen binding sites, some binding sites may be identical, so long as the protein has binding sites for two different antigens.
  • a full length antibody specifically binding to a first antigen consisting of: aa) two identical antibody heavy chains consisting of N-terminal to C-terminal direction of an antibody heavy chain variable domain (VH), an antibody constant heavy chain domain 1 (CHl), an antibody hinge region (HR), an antibody heavy chain constant domain 2 (CH2), and an antibody heavy chain constant domain 3 (CH3); and ab) two identical antibody light chains consisting in N-terminal to C-terminal direction of an antibody light chain variable domain (VL), and an antibody light chain constant domain (CL) (VL-CL).; and
  • the single chain Fab fragments consist of an antibody heavy chain variable domain (VH) and an antibody constant domain 1 (CHl), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, and wherein the said antibody domains and said linker have one of the following orders in N-terminal to C-terminal direction:
  • VH-CH 1-linker-VL-CL bb) VL-CL-linker-VH-CHl, be) VH-CL- linker- VL-CHl or bd) VL-CHl -linker- VH-CL;
  • linker is a peptide of at least 30 amino acids, preferably between 32 and 50 amino acids;
  • said peptide connector is a peptide of at least 5 amino acids, preferably between 10 and 50 amino acids.
  • Fab fragments ba) VH-CH 1-linker-VL-CL or bb) VL-CL-linker-VH-CHl, preferably bb) VL-CL-linker-VH-CHl, specifically binding to a second antigen are fused to said full length antibody via a peptide connector at the C-terminus of the heavy chain of said full length antibody, and the single chain Fab fragments are not disulfide stabilized.
  • One embodiment of the invention is a multispecific antibody according to the invention, wherein one or two single chain Fab fragments binding to a second antigen are fused to said full length antibody via a peptide connector at the C-terminus of the heavy chains of said full length antibody (bispecific antibody).
  • the multispecific antibody according to the invention comprises two identical single chain Fab fragments binding to a second antigen, which are either both fused to the heavy chain or which are both fused the light chain C- or N-termini. (bispecific antibody).
  • One embodiment of the invention is a multispecific antibody according to the invention, wherein two identical single chain Fab fragments VL-CL-linker-VH-
  • CHl or VH-CH 1-linker-VL-CL, preferably VL-CL-linker-VH-CHl, binding to a second antigen are fused with their N-termini to said full length antibody via a peptide connector at the two C-termini of the two heavy chains or at the two C-termini of the two light chains of said full length antibody (tetravalent, bispecific antibody).
  • said multispeciflc antibody (preferably said tetravalent, bispecific antibody) according to the invention is containing a full length IgG and two identical single chain Fab fragments according to the invention as described above and specifically binds human IGF-IR as well as to human EGFR.
  • These molecules are preferably based on the antigen-binding sites of the human anti-IGF-lR antibodies ⁇ IGF-1R> HUMAB Clone 18 (DSM ACC 2587; WO 2005/005635, abbreviated as ⁇ IGF-lR>Clonel8 or ⁇ IGF-1R> AK18) and humanized ⁇ EGFR>ICR62 (WO 2006/082515 abbreviated as ⁇ EGFR>ICR62).
  • These molecules simultaneously target and interfere with the action of two receptor tyrosine kinases on tumor cells. This dual activity causes a markedly improved anti-tumor activity compared to antibodies which interfere only with one of these receptors.
  • the design, composition, generation and characterization of such molecules is shown in Examples 1-6.
  • said full length antibody is specifically binding to IGFlR and comprises in the heavy chain variable domain a CDR3 region of SEQ ID NO: 1 , a
  • said single chain Fab fragment is specifically binding to EGFR and comprises in the heavy chain variable domain a CDR3 region of SEQ ID NO: 9, a CDR2 region of, SEQ ID NO: 10, and a CDRl region of SEQ ID NO: 11 , and in the light chain variable domain a CDR3 region of SEQ ID NO: 12, a CDR2 region of SEQ ID NO: 13, and a CDRl region of SEQ ID NO: 14.
  • such a multispecific antibody according to the invention is characterized in that i) said full length antibody is specifically binding to IGF-IR and comprises as heavy chain variable domain SEQ ID NO: 7, and as light chain variable domain SEQ ID NO: 8, and
  • said single chain Fab fragment is specifically binding to EGFR and comprises as heavy chain variable domain SEQ ID NO: 15, and as light chain variable domain a SEQ ID NO: 16.
  • said full length antibody is specifically binding to EGFR and comprises in the heavy chain variable domain a CDR3 region of SEQ ID NO: 9, a
  • said single chain Fab fragment is specifically binding to IGF-IR and comprises in the heavy chain variable domain a CDR3 region of SEQ ID NO: 1, a CDR2 region of SEQ ID NO: 2, and a CDRl region of SEQ ID NO:3, and in the light chain variable domain a CDR3 region of SEQ ID NO: 4, a CDR2 region of SEQ ID NO:5, and a CDRl region of SEQ ID NO:6.
  • said full length antibody is specifically binding to EGFR and comprises as heavy chain variable domain SEQ ID NO: 15, and as light chain variable domain a SEQ ID NO: 16, and
  • said single chain Fab fragment is specifically binding to IGFlR and comprises as heavy chain variable domain SEQ ID NO: 7, and as light chain variable domain SEQ ID NO: 8.
  • One embodiment of the invention is a multispecific antibody according to the invention, wherein two identical single chain Fab fragments VL-CL-linker-VH-
  • CHl or VH-CHl -linker- VL-CL, preferably VL-CL-linker-VH-CHl, binding to a second antigen are fused with their C-termini to said full length antibody via a peptide connector at the two N-termini of the two heavy chains or at the two N- termini of the two light chains of said full length antibody.
  • One embodiment of the invention is a multispecific antibody according to the invention, wherein one single chain Fab fragment binding to a second antigen is fused to said full length antibody via a peptide connector at the C or N-terminus of one heavy chain or one light chain of said full length antibody.
  • One embodiment of the invention is a multispecific antibody according to the invention, wherein one single chain Fab fragment binding to a second antigen is fused to said full length antibody via a peptide connector at the N-terminus of one heavy chain or one light chain of said full length antibody.
  • One embodiment of the invention is a multispecific antibody according to the invention, wherein one single chain Fab fragment binding to a second antigen is fused to said full length antibody via a peptide connector at the C-terminus of one heavy chain or one light chain of said full length antibody (see e.g. Fig 6).
  • the multispecific antibody according to the invention comprise two single chain Fab fragments binding to a second antigen and a third antigen (trispecific antibody) (see e.g. Fig 7).
  • the multispecific antibody according to the invention comprises
  • the full length antibodies of the invention comprise immunoglobulin constant regions of one or more immunoglobulin classes.
  • Immunoglobulin classes include IgG, IgM, IgA, IgD, and IgE isotypes and, in the case of IgG and IgA, their subtypes.
  • an full length antibody of the invention has a constant domain structure of an IgG type antibody.
  • the terms "monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of a single amino acid composition.
  • chimeric antibody refers to an antibody comprising a variable region, i.e., binding region, from one source or species and at least a portion of a constant region derived from a different source or species, usually prepared by recombinant DNA techniques. Chimeric antibodies comprising a murine variable region and a human constant region are preferred. Other preferred forms of “chimeric antibodies” encompassed by the present invention are those in which the constant region has been modified or changed from that of the original antibody to generate the properties according to the invention, especially in regard to CIq binding and/or Fc receptor (FcR) binding. Such chimeric antibodies are also referred to as "class-switched antibodies.”
  • Chimeric antibodies are the product of expressed immunoglobulin genes comprising DNA segments encoding immunoglobulin variable regions and DNA segments encoding immunoglobulin constant regions.
  • humanized antibody refers to antibodies in which the framework or
  • CDR complementarity determining regions
  • a murine CDR is grafted into the framework region of a human antibody to prepare the "humanized antibody.” See, e.g., Riechmann, L., et al., Nature 332 (1988) 323-327; and Neuberger, M.S., et al., Nature 314 (1985) 268-270.
  • Particularly preferred CDRs correspond to those representing sequences recognizing the antigens noted above for chimeric antibodies.
  • humanized antibodies encompassed by the present invention are those in which the constant region has been additionally modified or changed from that of the original antibody to generate the properties according to the invention, especially in regard to CIq binding and/or Fc receptor (FcR) binding.
  • FcR Fc receptor
  • human antibody is intended to include antibodies having variable and constant regions derived from human germ line immunoglobulin sequences.
  • Human antibodies are well-known in the state of the art (van Dijk, M. A., and van de Winkel, J., G., Curr. Opin. Chem. Biol. 5 (2001) 368-374).
  • Human antibodies can also be produced in transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire or a selection of human antibodies in the absence of endogenous immunoglobulin production.
  • Human antibodies can also be produced in phage display libraries (Hoogenboom, H. R., and Winter, GJ.
  • human antibody as used herein also comprises such antibodies which are modified in the constant region to generate the properties according to the invention, especially in regard to CIq binding and/or FcR binding, e.g. by "class switching” i.e. change or mutation of Fc parts (e.g. from IgGl to IgG4 and/or IgGl/IgG4 mutation.)
  • the multispecific antibody according to the invention comprises one or three single chain Fab fragments (or the in case of two not identical single chain fragments which ar attached both at the C-or N-termini of the either the heavy chain or light chain) which results in heterodimeric fusion peptides
  • the CH3 domains of said full length antibody according to the invention can be altered by the "knob-into-holes" technology which is described in detail with several examples in e.g. WO 96/027011, Ridgway, J.B., et al., Protein Eng 9 (1996) 617- 621 ; and Merchant, A.M., et al., Nat Biotechnol 16 (1998) 677-681.
  • said multispecific antibody according to the invention comprises only one single chain Fab fragment and is further is characterized in that
  • the CH3 domain of one heavy chain and the CH3 domain of the other heavy chain each meet at an interface which comprises an original interface between the antibody CH3 domains;
  • said interface is altered to promote the formation of the bivalent, bispecif ⁇ c antibody, wherein the alteration is characterized in that:
  • an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the interface of the CH3 domain of one heavy chain which is positionable in a cavity within the interface of the CH3 domain of the other heavy chain
  • an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the interface of the second CH3 domain within which a protuberance within the interface of the first CH3 domain is positionable.
  • amino acid residue having a larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), tryptophan (W).
  • amino acid residue having a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), valine (V).
  • both CH3 domains are further altered by the introduction of cysteine (C) as amino acid in the corresponding positions of each CH3 domain such that a disulfide bridge between both CH3 domains can be formed.
  • said multispecific antibody comprising only one single chain Fab fragment and is a trivalent, bispecific antibody.
  • Said trivalent, bispecific antibody comprises a T366W mutation in the CH3 domain of the "knobs chain” and T366S, L368A, Y407V mutations in the CH3 domain of the "hole chain”.
  • An additional interchain disulfide bridge between the CH3 domains can also be used (Merchant, A.M, et al., Nature Biotech 16 (1998) 677-681) e.g. by introducing a
  • said trivalent, bispecific antibody comprises Y349C, T366W mutations in one of the two CH3 domains and E356C, T366S, L368A, Y407V mutations in the other of the two CH3 domains or said trivalent, bispecific antibody comprises Y349C, T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains (the additional Y349C mutation in one CH3 domain and the additional E356C or S354C mutation in the other CH3 domain forming a interchain disulfide bridge) (numbering always according to EU index of Kabat).
  • knobs-in-holes technologies as described by EP 1870459A1, can be used alternatively or additionally.
  • a preferred example for said trivalent, bispecific antibody are R409D; K370E mutations in the CH3 domain of the "knobs chain” and D399K; E357K mutations in the CH3 domain of the "hole chain” (numbering always according to EU index of Kabat).
  • said trivalent, bispecific antibody (multispecific antibody comprising only one single chain Fab fragment) comprises a T366W mutation in the CH3 domain of the "knobs chain” and T366S, L368A, Y407V mutations in the CH3 domain of the "hole chain” and additionally R409D; K370E mutations in the CH3 domain of the "knobs chain” and D399K; E357K mutations in the CH3 domain of the "hole chain”.
  • said trivalent, bispecific antibody (multispecific antibody comprising only one single chain Fab fragment) comprises Y349C,
  • T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains or said trivalent, bispecific antibody comprises Y349C, T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains and additionally R409D; K370E mutations in the CH3 domain of the "knobs chain” and D399K; E357K mutations in the CH3 domain of the "hole chain”.
  • one embodiment of the invention is a multispecif ⁇ c antibody according to the invention, wherein one single chain Fab fragment binding to a second antigen is fused to said full length antibody via a peptide connector at the C- or N-terminus of one heavy chain or one light chain of said full length antibody (preferably the C-terminus of one heavy chain), wherein the full length antibody comprises a T366W mutation in one of the two CH3 domains and T366S, L368A, Y407V mutations in the other of the two CH3 domains.
  • Another embodiment of the invention is a multispecific antibody according to the invention, wherein one single chain Fab fragment binding to a second antigen is fused to said full length antibody via a peptide connector at the C- or N-terminus of one heavy chain or one light chain of said full length antibody (preferably the C-terminus of one heavy chain), wherein the full length antibody comprises Y349C, T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains, (see e.g. Fig 6).
  • Another embodiment of the invention is a multispecific antibody according to the invention, wherein one single chain Fab fragment binding to a second antigen is fused to said full length antibody via a peptide connector at the C- or N-terminus of one heavy chain or one light chain of said full length antibody (preferably the C-terminus of one heavy chain), wherein the full length antibody comprises Y349C, T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from a host cell such as a NSO or CHO cell or from an animal (e.g. a mouse) that is transgenic for human immunoglobulin genes or antibodies expressed using a recombinant expression vector transfected into a host cell.
  • recombinant human antibodies have variable and constant regions in a rearranged form.
  • the recombinant human antibodies according to the invention have been subjected to in vivo somatic hypermutation.
  • the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germ line VH and VL sequences, may not naturally exist within the human antibody germ line repertoire in vivo.
  • variable domain (variable domain of a light chain (VL), variable region of a heavy chain (VH) as used herein denotes each of the pair of light and heavy chains which is involved directly in binding the antibody to the antigen.
  • the domains of variable human light and heavy chains have the same general structure and each domain comprises four framework (FR) regions whose sequences are widely conserved, connected by three "hypervariable regions” (or complementarity determining regions, CDRs).
  • the framework regions adopt a ⁇ -sheet conformation and the CDRs may form loops connecting the ⁇ -sheet structure.
  • the CDRs in each chain are held in their three-dimensional structure by the framework regions and form together with the CDRs from the other chain the antigen binding site.
  • the antibody heavy and light chain CDR3 regions play a particularly important role in the binding specificity/affinity of the antibodies according to the invention and therefore provide a further object of the invention.
  • hypervariable region or "antigen-binding portion of an antibody” when used herein refer to the amino acid residues of an antibody which are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from the "complementarity determining regions” or "CDRs".
  • “Framework” or "FR” regions are those variable domain regions other than the hypervariable region residues as herein defined. Therefore, the light and heavy chains of an antibody comprise from N- to C-terminus the domains FRl, CDRl, FR2, CDR2, FR3, CDR3, and FR4. CDRs on each chain are separated by such framework amino acids. Especially, CDR3 of the heavy chain is the region which contributes most to antigen binding.
  • CDR and FR regions are determined according to the standard definition of Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991).
  • binding refers to the binding of the antibody to an epitope of the antigen in an in vitro assay, preferably in an plasmon resonance assay (BIAcore, GE-Healthcare Uppsala, Sweden) with purified wild-type antigen.
  • the affinity of the binding is defined by the terms ka (rate constant for the association of the antibody from the antibody/antigen complex), k D (dissociation constant), and K D (k ⁇ /ka).
  • Binding or specifically binding means a binding affinity (K D ) of 10 "8 mol/1 or less, preferably 10 "9 M to 10 "13 mol/1.
  • an multispecifc antibody according to the invention is specifically binding to each antigen for which it is specific with a binding affinity (K D ) of 10 ⁇ 8 mol/1 or less, preferably 10 ⁇ 9 M to 10 ⁇ 13 mol/1.
  • Binding of the antibody to the Fc ⁇ RIII can be investigated by a BIAcore assay (GE-Healthcare Uppsala, Sweden).
  • the affinity of the binding is defined by the terms ka (rate constant for the association of the antibody from the antibody/antigen complex), kp (dissociation constant), and K D (k ⁇ /ka).
  • epitope includes any polypeptide determinant capable of specific binding to an antibody.
  • epitope determinant include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and or specific charge characteristics.
  • An epitope is a region of an antigen that is bound by an antibody.
  • an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules.
  • constant region denotes the sum of the domains of an antibody other than the variable region.
  • the constant region is not involved directly in binding of an antigen, but exhibit various effector functions.
  • antibodies are divided in the classes: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses, such as IgGl, IgG2, IgG3, and IgG4, IgAl and IgA2.
  • the heavy chain constant regions that correspond to the different classes of antibodies are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the light chain constant regions (CL) which can be found in all five antibody classes are called K (kappa) and ⁇ (lambda).
  • constant region derived from human origin denotes a constant heavy chain region of a human antibody of the subclass IgGl, IgG2, IgG3, or IgG4 and/or a constant light chain kappa or lambda region.
  • constant regions are well known in the state of the art and e.g. described by Kabat, E.A., (see e.g. Johnson, G. and Wu, T.T., Nucleic Acids Res.
  • Pro238, Asp265, Asp270, Asn297 (loss of Fc carbohydrate), Pro329, Leu234, Leu235, Gly236, Gly237, Ile253, Ser254, Lys288, Thr307, Gln31 1, Asn434, and His435 are residues which, if altered, provide also reduced Fc receptor binding (Shields, R.L., et al., J. Biol. Chem. 276 (2001) 6591-6604; Lund, J., et al., FASEB J. 9 (1995) 115-119; Morgan, A., et al., Immunology 86 (1995) 319-324; EP 0 307 434).
  • an antibody according to the invention has a reduced FcR binding compared to an IgGl antibody and the full lenght parent antibody is in regard to FcR binding of IgG4 subclass or of IgGl or IgG2 subclass with a mutation in S228, L234, L235 and/or D265, and/ or contains the PVA236 mutation.
  • the mutations in the full length parent antibody are S228P, L234A, L235A, L235E and/or PVA236.
  • the mutations in the full length parent antibody are in IgG4 S228P and in IgGl L234A and L235A. Constant heavy chain regions shown in SEQ ID NO: 17 and 18.
  • the constant heavy chain region of the full length parent antibody is of SEQ ID NO: 17 with mutations L234A and L235A.
  • the constant heavy chain region of the full length parent antibody is of SEQ ID NO: 18 with mutation S228P.
  • the constant light chain region of the full length parent antibody is a kappa light chain region of SEQ ID NO: 19 or lambda light chain region.
  • the constant heavy chain region of the full length parent antibody is of SEQ ID NO: 17 or of SEQ ID NO: 18 with mutation S228P.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • CDC complement-dependent cytotoxicity
  • Such constant region binding sites are, e.g., characterized by the amino acids L234, L235, D270, N297, E318, K320, K322, P331, and P329 (numbering according to EU index of Kabat).
  • ADCC antibody-dependent cellular cytotoxicity
  • complement-dependent cytotoxicity denotes a process initiated by binding of complement factor CIq to the Fc part of most IgG antibody subclasses. Binding of CIq to an antibody is caused by defined protein-protein interactions at the so called binding site.
  • Fc part binding sites are known in the state of the art (see above). Such Fc part binding sites are, e.g., characterized by the amino acids L234, L235, D270, N297, E318, K320, K322, P331, and P329
  • Antibodies of subclass IgGl, IgG2, and IgG3 usually show complement activation including CIq and C3 binding, whereas IgG4 does not activate the complement system and does not bind CIq and/or C3.
  • the multispecific antibody according to the invention is characterized in that said full length antibody is of human IgGl subclass, or of human IgGl subclass with the mutations L234A and L235A.
  • the multispecific antibody according to the invention is characterized in that said full length antibody is of human IgG2 subclass.
  • the multispecific antibody according to the invention is characterized in that said full length antibody is of human IgG3 subclass.
  • the multispecific antibody according to the invention is characterized in that said full length antibody is of human IgG4 subclass or, of human IgG4 subclass with the additional mutation S228P.
  • the multispecific antibody according to the invention is characterized in that said full length antibody is of human IgGl subclass, of human IgG4 subclass with the additional mutation S228P.
  • the multispecific antibody according to the invention is characterized in that said full length antibody is modified (either by mutations in Fc regions or by glycoengineering) in a manner that increases affinity towards human Fc-gamma receptor Ilia to increase their competency to mediate ADCC. Methods to enhance the ADCC of antibodies by reducing the amount of fucose are described e.g.
  • the multispecific antibody according to the invention is characterized in that said full length antibody is an afucosylated of IgGl or IgG3 isotype wherein the amount of fucose is 60 % or less of the total amount of oligosaccharides (sugars) at Asn297 (which means that at least 40 % or more of the oligosaccharides of the Fc region at Asn297 are afucosylated).
  • the antibody according to the invention is produced by recombinant means.
  • one aspect of the current invention is a nucleic acid encoding the antibody according to the invention and a further aspect is a cell comprising said nucleic acid encoding an antibody according to the invention.
  • Methods for recombinant production are widely known in the state of the art and comprise protein expression in prokaryotic and eukaryotic cells with subsequent isolation of the antibody and usually purification to a pharmaceutically acceptable purity.
  • nucleic acids encoding the respective modified light and heavy chains are inserted into expression vectors by standard methods.
  • the multispecific antibodies according to the invention are suitably separated from the culture medium by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • DNA and RNA encoding the monoclonal antibodies is readily isolated and sequenced using conventional procedures.
  • the hybridoma cells can serve as a source of such DNA and RNA.
  • the DNA may be inserted into expression vectors, which are then transfected into host cells such as HEK 293 cells, CHO cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of recombinant monoclonal antibodies in the host cells.
  • Amino acid sequence variants (or mutants) of the multispecific antibody are prepared by introducing appropriate nucleotide changes into the antibody DNA, or by nucleotide synthesis. Such modifications can be performed, however, only in a very limited range, e.g. as described above. For example, the modifications do not alter the above mentioned antibody characteristics such as the IgG isotype and antigen binding, but may improve the yield of the recombinant production, protein stability or facilitate the purification.
  • host cell denotes any kind of cellular system which can be engineered to generate the antibodies according to the current invention.
  • HEK293 cells and CHO cells are used as host cells.
  • the expressions "cell,” “cell line,” and “cell culture” are used interchangeably and all such designations include progeny.
  • the words “transformants” and “transformed cells” include the primary subject cell and cultures derived therefrom without regard for the number of transfers. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Variant progeny that have the same function or biological activity as screened for in the originally transformed cell are included. Where distinct designations are intended, it will be clear from the context.
  • NSO cells Expression in NSO cells is described by, e.g., Barnes, L.M., et al., Cytotechnology 32 (2000) 109-123; Barnes, L.M., et al., Biotech. Bioeng. 73 (2001) 261-270.
  • Transient expression is described by, e.g., Durocher, Y., et al., Nucl. Acids. Res. 30 (2002) E9.
  • Cloning of variable domains is described by Orlandi, R., et al., Proc. Natl. Acad. Sci. USA 86 (1989) 3833-3837; Carter, P., et al., Proc. Natl. Acad. Sci.
  • control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
  • Eukaryotic cells are known to utilize promoters, enhancers and polyadenylation signals.
  • a nucleic acid is "operably linked" when it is placed in a functional relationship with another nucleic acid sequence.
  • DNA for a pre-sequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a pre-protein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or
  • a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • "operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • hydrophobic interaction or aromatic adsorption chromatography e.g. with phenyl-sepharose, aza-arenophilic resins, or m-aminophenylboronic acid
  • metal chelate affinity chromatography e.g. with Ni(II)- and Cu(II)-affinity material
  • size exclusion chromatography e.g. with electrophoretical methods (such as gel electrophoresis, capillary electrophoresis)
  • transfection refers to process of transfer of a vectors/nucleic acid into a host cell. If cells without daunting cell wall barriers are used as host cells, transfection is carried out e.g. by the calcium phosphate precipitation method as described by Graham, F. L., and van der Eb, A.J., Virology 52 (1973) 456-467. However, other methods for introducing DNA into cells such as by nuclear injection or by protoplast fusion may also be used. If prokaryotic cells or cells which contain substantial cell wall constructions are used, e.g. one method of transfection is calcium treatment using calcium chloride as described by Cohen, S.N., et al., PNAS. 69 (1972) 2110-2114.
  • expression refers to the process by which a nucleic acid is transcribed into mRNA and/or to the process by which the transcribed mRNA (also referred to as transcript) is subsequently being translated into peptides, polypeptides, or proteins.
  • the transcripts and the encoded polypeptides are collectively referred to as gene product. If the polynucleotide is derived from genomic DNA, expression in a eukaryotic cell may include splicing of the mRNA.
  • a "vector” is a nucleic acid molecule, in particular self-replicating, which transfers an inserted nucleic acid molecule into and/or between host cells.
  • the term includes vectors that function primarily for insertion of DNA or RNA into a cell (e.g., chromosomal integration), replication of vectors that function primarily for the replication of DNA or RNA, and expression vectors that function for transcription and/or translation of the DNA or RNA. Also included are vectors that provide more than one of the functions as described.
  • An "expression vector” is a polynucleotide which, when introduced into an appropriate host cell, can be transcribed and translated into a polypeptide.
  • expression system usually refers to a suitable host cell comprised of an expression vector that can function to yield a desired expression product.
  • the multispecific antibodies according to the invention have improved characteristics such as biological or pharmacological activity, pharmacokinetic properties or toxicity. They can be used e.g. for the treatment of diseases such as cancer.
  • One aspect of the invention is a pharmaceutical composition comprising an antibody according to the invention.
  • Another aspect of the invention is the use of an antibody according to the invention for the manufacture of a pharmaceutical composition.
  • a further aspect of the invention is a method for the manufacture of a pharmaceutical composition comprising an antibody according to the invention.
  • the present invention provides a composition, e.g. a pharmaceutical composition, containing an antibody according to the present invention, formulated together with a pharmaceutical carrier.
  • One embodiment of the invention is the multispecific, preferably bispecif ⁇ c antibody according to the invention for the treatment of cancer.
  • Another aspect of the invention is said pharmaceutical composition for the treatment of cancer.
  • Another aspect of the invention is the use of an antibody according to the invention for the manufacture of a medicament for the treatment of cancer.
  • Another aspect of the invention is method of treatment of patient suffering from cancer by administering an antibody according to the invention to a patient in the need of such treatment.
  • pharmaceutical carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g. by injection or infusion).
  • a composition of the present invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. To administer a compound of the invention by certain routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • Pharmaceutical carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • cancer refers to proliferative diseases, such as lymphomas, lymphocytic leukemias, lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ure
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • composition must be sterile and fluid to the extent that the composition is deliverable by syringe.
  • carrier preferably is an isotonic buffered saline solution.
  • Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition.
  • SEQ ID NO: 8 light chain variable domain, ⁇ IGF- 1 R> HUMAB-Clone 18 SEQ ID NO: 9 heavy chain CDR3, humanized ⁇ EGFR>ICR62 SEQ ID NO: 10 heavy chain CDR2, humanized ⁇ EGFR>ICR62 SEQ ID NO: 11 heavy chain CDRl, humanized ⁇ EGFR>ICR62 SEQ ID NO: 12 light chain CDR3, humanized ⁇ EGFR>ICR62 SEQ ID NO: 13 light chain CDR2, humanized ⁇ EGFR>ICR62 SEQ ID NO: 14 light chain CDRl, humanized ⁇ EGFR>ICR62 SEQ ID NO: 15 heavy chain variable domain, humanized ⁇ EGFR>ICR62-I-
  • Figure 1 Schematic structure of a full length antibody without CH4 domain specifically binding to a first antigen 1 with two pairs of heavy and light chain which comprise variable and constant domains in a typical order.
  • Figure 2 Schematic structure of the four possible single chain Fab fragments specifically binding e.g. to second antigen 2
  • Figure 3 Schematic structure of a multispecific antibodies according to the invention comprising a full length antibody specifically binding to a first antigen 1 and two single chain Fabs specifically binding to second antigen 2- bispecific tetravalent example
  • Bispecific antibodies according to the invention comprising a full length antibody specifically binding to IGF-IR and two identical single chain Fabs specifically binding to EGFR - ScFab-XGFRl molecules A, B, C, and D and expression levels after purification
  • scFab VH-CHl -linker- VL-CL fused to C-Terminus of light chain
  • D scFab (VH-CHl -linker- VL-CL with additional VH44- VLlOO disulfide bridge fused) to C-Terminus of light chain
  • Bispecific antibodies according to the invention comprising a full lenght antibody specifically binding to EGFR and two identical single chain Fabs specifically binding to IGF- 1 R -ScFab-
  • scFab VH-CHl -linker- VL-CL fused to C-Terminus of heavy chain
  • B scFab (VH-CHl -linker- VL-CL with additional VH44- VLlOO disulfide bridge fused) to C-Terminus of heavy chain
  • FIG 6 Schematic structure of a multispecific antibodies according to the invention comprising a full length antibody specifically binding to a first antigen 1 and one single chain Fab specifically binding to a second antigen 2 - bispecific trivalent example with knobs and holes
  • Figure 7 Schematic structure of a multispecific antibodies according to the invention comprising a full length antibody specifically binding to a first antigen 1 one single chain Fab specifically binding to a second antigen 2 and one single chain Fab specifically binding to a third antigen 3- trispecific tetravalent example with knobs and holes
  • FIG. 9 HP-SEC analyses of scFab containing bispecific antibody derivatives scFab-XGFRl Fig. 9a: scFab-XGFRl-4720; 7.7 %, Aggregates (marked within box)
  • Fig. 9b scFab-XGFR 1-4721; 3.5 %, Aggregates (marked within box)
  • Figure 10 Binding of scFab-XGFRl and scFab-XGFR2 to EGFR and
  • Fig 10a Biacore diagram-Binding of scFab-XGFRl_2720 to
  • Fig 10b Biacore diagram-Binding of scFab-XGFRl_2720 to
  • Fig 10c Biacore diagram-Binding of scFab-XGFR2_2720 to
  • Fig 1Od Biacore diagram-Binding of scFab-XGFR2_2720 to
  • IGF-IR 5 KD I l nM
  • FIG 11 Scheme - Binding of scFab-XGFR to cells analyzed by FACS competition assays with following general procedure: -add ⁇ IGF1R> Mab labeled with-Alexa647 (1 ⁇ g/mL) +unlabeled scFab-XGFR (100 ⁇ g/mL - 0,001 ⁇ g/mL )in parallel
  • Fig 12a Comparison of IC50 values of ⁇ IGF-lR>Clonel8 (0,18 ⁇ g/ml) and scFab-XGFR_2721 (0,15 ⁇ g/ml)
  • Desired gene segments were prepared from oligonucleotides made by chemical synthesis.
  • the 600 - 1800 bp long gene segments, which are flanked by singular restriction endonuclease cleavage sites, were assembled by annealing and ligation of oligonucleotides including PCR amplification and subsequently cloned via the indicated restriction sites e.g. BamHI/BstEII, BamHI/BsiWI, BstEII/Notl or BsiWI/Notl into a pcDNA 3.1/Zeo(+) (Invitrogen) based on a pUC cloning vector.
  • the DNA sequences of the subcloned gene fragments were confirmed by DNA sequencing. Gene synthesis fragments were ordered according to given specifications at Geneart (Regensburg, Germany).
  • DNA sequences were determined by double strand sequencing performed at Sequiserve GmbH (Vaterstetten, Germany). DNA and protein sequence analysis and sequence data management
  • GCG Genetics Computer Group, Madison, Wisconsin
  • Invitrogens Vector NTl Advance suite version 9.1 was used for sequence creation, mapping, analysis, annotation and illustration.
  • the multispecific antibodies were expressed by transient transfection of human embryonic kidney 293 -F cells using the FreeStyleTM 293 Expression System according to the manufacturer's instruction (Invitrogen, USA). Briefly, suspension FreeStyleTM 293 -F cells were cultivated in FreeStyleTM 293 Expression medium at 37°C/8 % CO 2 and the cells were seeded in fresh medium at a density of 1-2x10 6 viable cells/ml on the day of transfection.
  • the DNA-293fectinTM complexes were prepared in Opti-MEM ® I medium (Invitrogen, USA) using 333 ⁇ l of 293fectinTM (Invitrogen, Germany) and 250 ⁇ g of heavy and light chain plasmid DNA in a 1 :1 molar ratio for a 250 ml final transfection volume.
  • Bispecific antibody containing cell culture supernatants were clarified 7 days after transfection by centrifugation at 14000 g for 30 minutes and filtration through a sterile filter (0.22 ⁇ m).
  • the protein concentration of purified antibodies and derivatives was determined by determining the optical density (OD) at 280 nm with the OD at 320nm as the background correction, using the molar extinction coefficient calculated on the basis of the amino acid sequence according to Pace, CN. , et. al., Protein Science, 4 (1995) 2411-2423.
  • the concentration of antibodies and derivatives in cell culture supernatants was measured by affinity HPLC chromatography. Briefly, cell culture supernatants containing antibodies and derivatives that bind to Protein A were applied to an Applied Biosystems Poros A/20 column in 200 mM KH2PO4, 100 mM sodium citrate, pH 7.4 and eluted from the matrix with 200 mM NaCl, 100 mM citric acid, pH 2,5 on an UltiMate 3000 HPLC system (Dionex). The eluted protein was quantified by UV absorbance and integration of peak areas. A purified standard IgGl antibody served as a standard.
  • the secreted antibodies were purified from the supernatant in two steps by affinity chromatography using Protein A-SepharoseTM (GE Healthcare, Sweden) and Superdex200 size exclusion chromatography. Briefly, the bispecific and trispecific antibody containing clarified culture supernatants were applied on a HiTrap
  • the eluted protein fractions were pooled, concentrated with an Amicon Ultra centrifugal filter device (MWCO: 30 K, Millipore) to a volume of 3 ml and loaded on a Superdex200 HiLoad 120 ml 16/60 gel filtration column (GE Healthcare, Sweden) equilibrated with 2OmM Histidin, 140 mM NaCl, pH 6.0. Monomelic antibody fractions were pooled, snap-frozen and stored at - 80°C. Parts of the samples were provided for subsequent protein analytics and characterization.
  • MWCO Amicon Ultra centrifugal filter device
  • the protein concentration of purified protein samples was determined by measuring the optical density (OD) at 280 nm, using the molar extinction coefficient calculated on the basis of the amino acid sequence.
  • the purity of the bispecific antibodies were analyzed by SDS-PAGE in the presence and absence of a reducing agent (5 mM 1 ,4-dithiotreitol) and staining with Coomassie brilliant blue.
  • the NuP AGE® Pre-Cast gel system (Invitrogen, USA) was used according to the manufacturer's instruction (4-20 % Tris-Glycine gels).
  • the aggregate content of bispecific antibody samples was analyzed by high-performance SEC on an
  • Glycosidase F (Roche Molecular Biochemicals).
  • bispecific antibodies comprising a full length antibody binding to a first antigen (IGF-IR or EGFR) with two single chain Fab fragments binding to a second different antigen (the other of IGF-IR or EGFR) connected via peptide connector to the full length antibody (either both single chain Fab fragments at the two C-termini of the heavy chain or at the two C-termini of the light chain) are exemplified.
  • the antibody domains and the linker in said single chain Fab fragment have the following order in N-terminal to C-terminal direction: VL-CL-linker-VH-CHl.
  • VL-CL and VH- CHl comprising the VH and VL of the respective antigen binding site were linked by a glycine serine (G4S)n single-chain-linker to give a single chain Fab fragment VL-CL-linker-VH-CHl, which was attached to the C- terminus of the antibody heavy or light chain using (G4S)n linker.
  • G4S glycine serine
  • cystine residues were introduced in the VH (including Kabat position 44,) and VL (including Kabat position 100) domain of the single chain Fab fragment according to techiques as described earlier (e.g. WO 94/029350; Reiter,
  • Table 1 The different bispecific anti IGFlR and antiEGFR tetravalent antibody formats with C- terminal single chain Fab fragment attachments and the corresponding scFab-Ab-nomenclature.
  • the bispecific antibodies were expressed by transient transfection of human embryonic kidney 293 -F cells using the FreeStyleTM 293 Expression System according to the manufacturer's instruction (Invitrogen, USA). Briefly, suspension
  • FreeStyleTM 293 -F cells were cultivated in FreeStyleTM 293 Expression medium at 37°C/8 % CO 2 and the cells were seeded in fresh medium at a density of 1-2x10 6 viable cells/ml on the day of transfection.
  • the DNA-293fectinTM complexes were prepared in Opti-MEM ® I medium (Invitrogen, USA) using 333 ⁇ l of 293fectinTM (Invitrogen, Germany) and 250 ⁇ g of heavy and light chain plasmid DNA in a 1 :1 molar ratio for a 250 ml final transfection volume.
  • Recombinant antibody derivative containing cell culture supernatants were clarified 7 days after transfection by centrifugation at 14000 g for 30 minutes and filtration through a sterile filter (0.22 ⁇ m). Supernatants were stored at -20° C until purification.
  • the secreted antibody derivatives were purified from the supernatant in two steps by affinity chromatography using Protein A-SepharoseTM (GE Healthcare, Sweden) and Superdex200 size exclusion chromatography. Briefly, the bispecific and trispecific antibody containing clarified culture supernatants were applied on a HiTrap ProteinA HP (5 ml) column equilibrated with PBS buffer (10 mM Na 2 HPO 4 , 1 mM KH 2 PO 4 , 137 mM NaCl and 2.7 mM KCl, pH 7.4). Unbound proteins were washed out with equilibration buffer.
  • PBS buffer 10 mM Na 2 HPO 4 , 1 mM KH 2 PO 4 , 137 mM NaCl and 2.7 mM KCl, pH 7.4
  • the antibody derivatives were eluted with 0.1 M citrate buffer, pH 2.8, and the protein containing fractions were neutralized with 0.1 ml 1 M Tris, pH 8.5. Then, the eluted protein fractions were pooled, concentrated with an Amicon Ultra centrifugal filter device (MWCO: 30 K, Millipore) to a volume of 3 ml and loaded on a Superdex200 HiLoad 120 ml 16/60 gel filtration column (GE Healthcare, Sweden) equilibrated with 2OmM Histidin, 140 mM NaCl, pH 6.0. Monomelic antibody fractions were pooled, snap-frozen and stored at -80 0 C. Part of the samples were provided for subsequent protein analytics and characterization. Exemplary SDS-PAGE analyses of purified proteins and profiles of HP-Size Exclusion Chromatography (SEC) of bispecific antibody derivatives are shown in Figures 8 and 9.
  • SEC HP-Size Exclusion Chromatography
  • Figure 5 lists the expression yields that were observed in transient expression systems: All designed antibody derivatives could be expressed and purified in sufficient amounts for further analyses. For comparison reasons a tetravalent bispecific antibody based on a full length antibody to which two scFv fragments are fused via a peptide linker at the C-terminus of the heavy chain as described in WO 1995/009917 and M ⁇ ller D., et al, Handbook of Therapeutic antibodies, Part IH, Chapter 2, (2008) 345-378 was prepared and named. Instead of the scFab which it bears instead of . As heavy chain variable domain VH for the ⁇ IGF-1R> antigen binding site SEQ ID NO: 15 was used.
  • the bispecific single chain Fv molecule XGFRl -2320 had a final yield after purification of 0.27 mg whereas the corresponding single chain Fab molecule XGFRl -2720 had a final yield of 6.8 mg (see Figure 4, compound A), which represents a more than 200 fold increase in yield.
  • HP-Size exclusion chromatography analysis was performed to determine the amounts of aggregates that are present in preparation of recombinant antibody derivatives. For that, bispecific antibody samples were analyzed by high- performance SEC on an UltiMate 3000 HPLC system (Dionex) using a Superdex
  • the binding properties bispecific ⁇ IGF-1R-EGFR> antibodies were analyzed by surface plasmon resonance (SPR) technology using a Biacore TlOO instrument (GE Healthcare Bio-Sciences AB, Uppsla). This system is well established for the study of molecule interactions. It allows a continuous real-time monitoring of ligand/analyte bindings and thus the determination of association rate constants
  • Capturing anti -human IgG antibody was immobilized on the surface of a Cl biosensorchip using amine-coupling chemistry.
  • Flow cells were activated with a 1 :1 mixture of 0.1 M N-hydroxysuccinimide and 0.1 M 3-(N 5 N- dimethylamino)propyl-N-ethylcarbodiimide at a flow rate of 5 ⁇ l/min.
  • Anti-human IgG antibody was injected in sodium acetate, pH 5.0 at 5 ⁇ g/ml, which resulted in a surface density of approximately 200 RU.
  • a reference control flow cell was treated in the same way but with vehicle buffers only instead of the capturing antibody.
  • the bispecific antibodies were diluted in HBS-P and injected at a flow rate of 5 ⁇ l/min.
  • the contact time (association phase) was 1 min for the antibodies at a concentration between 1 and 5 nM.
  • EGFR-ECD was injected at increasing concentrations of 1.2, 3.7, 11.1, 33.3, 100 and 300 nM, IGF-IR at concentrations of
  • the contact time (association phase) was 3 min, the dissociation time (washing with running buffer) 5 min for both molecules at a flowrate of 30 ⁇ l/min. All interactions were performed at 25 °C (standard temperature).
  • the regeneration solutions of 0.85 % phosphoric acid and 5 mM sodium hydroxide were injected each for 60 s at 5 ⁇ l/min flow to remove any non- covalently bound protein after each binding cycle. Signals were detected at a rate of one signal per second. Samples were injected at increasing concentrations.
  • FIG. 11 shows the experimental set-up that we used to test binding capabilities of scFab containing bispecific XGFR derivatives on A549 cancer cells.
  • A549 cells which express the antigens EGFR as well IGFlR were detached and counted. 1.5xl ⁇ e5 cells were seeded per well of a conical 96-well plate.
  • Mf ⁇ was determined at least in duplicates of two independent stainings. Flow cytometry spectra were further processed using the FlowJo software (TreeStar). Half-maximal binding was determined using XLFit 4.0 (IDBS) and the dose response one site model 205.
  • IDBS XLFit 4.0
  • IGF-I receptor IGF-IR
  • time-course experiments and subsequent ELISA analysis with IGF-IR and EGFR specific antibodies were performed.
  • a 6 well plate was inoculated with 1 ml per well human tumor cells (H322M, 5 x 10 5 cells/ml) in RPMI 1640 supplemented with 10 % FCS (PAA, Cat. No. El 5- 039) and 1 % PenStrep. 3 ml medium were added to each well and the cells were cultivated for 24 hours at 37°C and 5 % CO 2 .
  • the medium was carefully removed and replaced by 2ml 100 nM XGFR antibodies diluted in RPMI-VM medium. In control wells, medium was replaced by either medium and buffer without antibody and medium with control antibodies ( ⁇ IGF- 1R> HUMAB Clone 18 and ⁇ EGFR>ICR62 final concentration 100 nM). Cells were incubated at 37°C and 5 % CO 2 and individual plates were taken out for further processing after 24 hours.
  • MES-lysis buffer MES, 10 mM Na 3 VO 4 , and Complete ® protease inhibitor. After one hour the cells were detached on ice using a cell scraper (Corning, Cat. No. 3010) and the well contents transferred to Eppendorf reaction tubes. Cell fragments were removed by centrifugation for 10 minutes at 13000 rpm and 4°C.
  • the 96 well microtitreplates were prepared according to the protocol (DuoSet ELISA for Human EGFR, RnD systems Cat. No. DY231).
  • the Human EGFR goat antibody 144 ⁇ g/ml in PBS was diluted 1 :180 in PBS and 100 ⁇ l/well was added to the MTP.
  • the MTP was incubated overnight at room temperature with agitation.
  • the plates were washed 3 times with PBS supplemented with 0.1 % Tween ® 20 and blocked with 300 ⁇ l/well of PBS, 3 % BSA and 0.1 % Tween ® 20 solution for 1 hour (h) at room temperature (RT) with aggitation.
  • the plates were washed 3 times with PBS supplemented with 0.1 % Tween ® 20.
  • the amount of protein in the cell lysates was determined using the BCA Protein Assay kit (Pierce), the cell lysates were then adjusted to a protein concentration of 0.04 mg/ml with MES-lysis buffer supplemented with 100 mM Na 3 VO 4 1 :100 and Complete ® protease inhibitor 1 :20 and 100 ⁇ l per well of the lysate was added to the pre-prepared MTP. For background measurement 100 ⁇ l lysis buffer was added to the well in the MTP.
  • a second cell lysate concentration was used at 0.025 mg/ml the lysate was dilute 1 :2 and 100 ⁇ l was added per well to the pre-prepared MTP.
  • the MTP were incubated for a further 2 hour at RT with agitation and then washed 3 times with PBS with 0.1 % Tween ® 20 solution.
  • the detection antibody for EGFR was human EGFR goat biotinylated antibody at a concentration of 36 ⁇ g/ml diluted 1 :180 in PBS, 3 % BSA and 0.2 % Tween ® 20. 100 ⁇ l per well was added and incubated at RT for 2 hours with agitation.
  • MTP was then washed three times with 200 ⁇ l per well of PBS with 0.1 % Tween ® 20 solution. Then Streptavidin-HRP 1 :200 in PBS, 3 % BSA and 0.2 % Tween ® 20 100 ⁇ l per well was added and incubated with agitation for 20 minutes at RT. The plate was then washed six times with PBS with 0.1 % Tween ® 20 solution. 100 ⁇ l per well of 3,3'-5,5'-Tetramethylbenzidin (Roche, BM-Blue ID-
  • the streptavidin-MTP (Roche ID. No.: 11965891001) was prepared by adding 100 ⁇ l per well of the antibody AKla-Biotinylated (Genmab, Denmark) which was diluted 1 :200 in PBS, 3 % BSA and 0.2 % Tween ® 20. The streptavidin-MTP was incubated for 1 hour at RT with agitation and then washed three times with 200 ⁇ l per well of PBS with 0.1 % Tween ® 20 solution.
  • the amount of protein in the cell lysates was determined using the BCA Protein
  • the cell lysates were then adjusted to a protein concentration of 0.3 mg/ml with 5OmM Tris pH 7.4, 100 mM Na 3 VO 4 1 :100 and Complete ® protease inhibitor 1 :20 and 100 ⁇ l per well of the lysate was added to the pre- prepared streptavidin-MTP.
  • a second cell lysate concentration was used at 0.15 mg/ml the lysate was dilute and
  • the MTP were incubated for a further 1 hour at RT with agitation and then washed 3 times with PBS with 0.1 % Tween ® 20 solution.
  • the detection antibody for IGF-IR was human IGF-1R0 rabbit antibody (Santa).
  • the bispecific antibodies scFab-XGFR_2720 showed an improved downregulation of EGFR compared to the parent ⁇ EGFR>ICR62 antibody alone.
  • the human anti-IGF-lR antibody ⁇ IGF-1R> HUMAB Clone 18 inhibits the growth of tumor cell lines that express the IGFlR (WO 2005/005635).
  • the humanized rat anti-EGFR antibody ⁇ EGFR>ICR62 has been shown to inhibit the growth of tumor cell lines that express EGFR (WO 2006/082515).
  • H322M cells (5000 cells/well) were cultured in RPMI 1640 media supplemented with 10 % FCS on poly-HEMA (poly(2-hydroxyethylmethacrylate)) coated dishes to prevent adherence to the plastic surface. Under these conditions H322M cells form dense spheroids that grow three dimensionally (a property that is called anchorage independence). These spheroids resemble closely the three dimensional histoarchitecture and organization of solid tumors in-situ. Spheroid cultures were incubated for 7 days in the presence of 100 nM antibodies. The Celltiter Glow luminescence assay was used to measure growth inhibition. When H322M spheroid cultures were treated with ⁇ IGF-1R> HUMAB-Clonel8 an inhibition in growth could be observed.
  • poly-HEMA poly(2-hydroxyethylmethacrylate)
  • Figure 15 shows that the application of 10OnM ⁇ IGF-1R> HUMAB-Clonel8 reduced the cell growth by 72 %, and that the application of 10OnM ⁇ EGFR>ICR62 reduced the cell growth by 77 % in the same assay.
  • the simultaneous application of both antibodies resulted in a complete decrease of cell viability (100 % inhibition).
  • Application of various scFab-XGFRl -variants at molar concentration of 10OnM resulted in a higher growth inhibition that was more pronounced that that observed with single molecules alone. In fact, at an antibody concentration of 100 nM, various scFab-XGFRl -variants showed complete (100 %) inhibition of cell growth, while application of single modules caused only partial inhibition.
  • scFab-XGFRl molecules have a profoundly increased growth inhibitory activity compared to IgGs that solely interfere with either EGFR signaling or IGFlR signaling.

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Abstract

La présente invention porte sur des anticorps multispécifiques, notamment bispécifiques, renfermant des anticorps de longueur entière et des fragments Fab à chaîne unique, sur leurs procédés de préparation, sur des compositions pharmaceutiques contenant lesdits anticorps et sur leurs utilisations.
PCT/EP2010/002004 2009-04-02 2010-03-30 Anticorps multispécifiques renfermant des anticorps de longueur entière et des fragments fab à chaîne unique Ceased WO2010112193A1 (fr)

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CN201080015592.4A CN102369215B (zh) 2009-04-02 2010-03-30 包含全长抗体和单链Fab片段的多特异性抗体
BRPI1014089A BRPI1014089A2 (pt) 2009-04-02 2010-03-30 anticorpos multiespecíficos que compreendem anticorpos de comprimento completo e fragmentos fab de cadeia simples
KR1020117025868A KR101431318B1 (ko) 2009-04-02 2010-03-30 전장 항체 및 단일쇄 ｆａｂ 단편을 포함하는 다중특이성 항체
JP2012502505A JP5501439B2 (ja) 2009-04-02 2010-03-30 完全長抗体と単鎖Ｆａｂフラグメントとを含む多重特異的抗体
CA 2756244 CA2756244A1 (fr) 2009-04-02 2010-03-30 Anticorps multispecifiques renfermant des anticorps de longueur entiere et des fragments fab a chaine unique
EP10711847.3A EP2414391B1 (fr) 2009-04-02 2010-03-30 Anticorps multispécifiques renfermant des anticorps complets et des fragments fab monocaténaires
HK12108390.5A HK1167669B (en) 2009-04-02 2010-03-30 Multispecific antibodies comprising full length antibodies and single chain fab fragments
RU2011143905/10A RU2598248C2 (ru) 2009-04-02 2010-03-30 Полиспецифичные антитела, включающие антитела полной длины и одноцепочечные фрагменты fab
MX2011010159A MX2011010159A (es) 2009-04-02 2010-03-30 Anticuerpos multiespecificos que comprenden anticuerpos de longitud completa y fragmentos fab de cadena sencilla.
SG2011071479A SG175004A1 (en) 2009-04-02 2010-03-30 Multispecific antibodies comprising full length antibodies and single chain fab fragments
AU2010230563A AU2010230563A1 (en) 2009-04-02 2010-03-30 Multispecific antibodies comprising full length antibodies and single chain Fab fragments
IL214756A IL214756A0 (en) 2009-04-02 2011-08-18 Multispecific antibodies comprising full length antibodies and single chain fab fragments
ZA2011/06666A ZA201106666B (en) 2009-04-02 2011-09-12 Multispecific antibodies comprising full length antibodies and single chain fab fragments

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